Regulation of the cell cycle by focal adhesion kinase.
Regulation of the cell cycle by focal adhesion kinase.
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通过局灶性激酶调节细胞周期。
DOI：
10.1083/jcb.143.7.1997
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发表时间：
1998-12-28
影响因子：
7.8
通讯作者：
Guan, J L
中科院分区：
文献类型：
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作者：
Zhao, J H;Reiske, H;Guan, J L
在这篇报道中，我们利用四环素调控的外源FAK及其突变体的表达，分析了整合素信号通过FAK在细胞周期调控中的潜在作用和机制。我们发现野生型FAK的过表达加速了细胞周期从G1向S的转变。相反，过表达显性负性粘着斑激酶突变体ΔC14可以抑制细胞周期在G1期的进展，这种抑制需要在ΔC14中使用Y397。生化分析表明，FAK突变体ΔC14定位错误，与内源性FAK在焦点接触处竞争结合Src和Fyn等信号分子，导致ERK在细胞黏附中的激活降低，成为显性负突变。与此一致，我们还观察到FAK Y397F突变体和FRNK在原代人包皮成纤维细胞瞬时转染实验中抑制了BrdU的掺入和ERK的激活，但FRNKΔC14没有。我们还发现，ΔC14阻断了细胞周期蛋白D1的上调，诱导了p21的表达，而野生型FAK则增加了细胞周期蛋白D1的表达，降低了p21的表达。综上所述，这些结果已经确认FAK及其相关的信号通路是整合素调节细胞周期的媒介。
In this report, we have analyzed the potential role and mechanisms of integrin signaling through FAK in cell cycle regulation by using tetracycline-regulated expression of exogenous FAK and mutants. We have found that overexpression of wild-type FAK accelerated G1 to S phase transition. Conversely, overexpression of a dominant-negative FAK mutant ΔC14 inhibited cell cycle progression at G1 phase and this inhibition required the Y397 in ΔC14. Biochemical analyses indicated that FAK mutant ΔC14 was mislocalized and functioned as a dominant-negative mutant by competing with endogenous FAK in focal contacts for binding signaling molecules such as Src and Fyn, resulting in a decreases of Erk activation in cell adhesion. Consistent with this, we also observed inhibition of BrdU incorporation and Erk activation by FAK Y397F mutant and FRNK, but not FRNKΔC14, in transient transfection assays using primary human foreskin fibroblasts. Finally, we also found that ΔC14 blocked cyclin D1 upregulation and induced p21 expression, while wild-type FAK increased cyclin D1 expression and decreased p21 expression. Taken together, these results have identified FAK and its associated signaling pathways as a mediator of the cell cycle regulation by integrins.